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Objective: The incidence of paediatric inflammatory bowel disease (IBD) has been increasing over 25 years; however, contemporary trends are not established and the impact of COVID-19 on case rates is unclear. Methods: Data from Southampton Children's hospital prospective IBD database were retrieved for 2002-2021. Incidence rates were calculated based on referral area populations and temporal trends analysed. Disease prevalence for those aged -6, driven by Crohn's disease, β = 0.732, P = 0.00024 and ulcerative colitis, β = 0.816, P = 0.000011. There was no change in IBDU incidence, β = 0.230, P = 0.33. From 2002-2021, 51 patients were diagnosed -7). There was no significant change in incidence of IBD in

Supplementary Figure Legend from Assessing the Activity of Cediranib, a VEGFR-2/3 Tyrosine Kinase Inhibitor, against VEGFR-1 and Members of the Structurally Related PDGFR Family

Supplementary Tables 1-3 from Assessing the Activity of Cediranib, a VEGFR-2/3 Tyrosine Kinase Inhibitor, against VEGFR-1 and Members of the Structurally Related PDGFR Family

Supplementary Figure 1 from Assessing the Activity of Cediranib, a VEGFR-2/3 Tyrosine Kinase Inhibitor, against VEGFR-1 and Members of the Structurally Related PDGFR Family

Cediranib is a potent inhibitor of the VEGF receptor (VEGFR)-2 and VEGFR-3 tyrosine kinases. This study assessed the activity of cediranib against the VEGFR-1 tyrosine kinase and the platelet-derived growth factor receptor (PDGFR)-associated kinases c-Kit, PDGFR-α, and PDGFR-β. Cediranib inhibited VEGF-A–stimulated VEGFR-1 activation in AG1-G1-Flt1 cells (IC50 = 1.2 nmol/L). VEGF-A induced greatest phosphorylation of VEGFR-1 at tyrosine residues Y1048 and Y1053; this was reversed by cediranib. Potency against VEGFR-1 was comparable with that previously observed versus VEGFR-2 and VEGFR-3. Cediranib also showed significant activity against wild-type c-Kit in cellular phosphorylation assays (IC50 = 1–3 nmol/L) and in a stem cell factor–induced proliferation assay (IC50 = 13 nmol/L). Furthermore, phosphorylation of wild-type c-Kit in NCI-H526 tumor xenografts was reduced markedly following oral administration of cediranib (≥1.5 mg/kg/d) to tumor-bearing nude mice. The activity of cediranib against PDGFR-β and PDGFR-α was studied in tumor cell lines, vascular smooth muscle cells (VSMC), and a fibroblast line using PDGF-AA and PDGF-BB ligands. Both receptor phosphorylation (IC50 = 12–32 nmol/L) and PDGF-BB–stimulated cellular proliferation (IC50 = 32 nmol/L in human VSMCs; 64 nmol/L in osteosarcoma cells) were inhibited. In vivo, ligand-induced PDGFR-β phosphorylation in murine lung tissue was inhibited by 55% following treatment with cediranib at 6 mg/kg but not at 3 mg/kg or less. In contrast, in C6 rat glial tumor xenografts in mice, ligand-induced phosphorylation of both PDGFR-α and PDGFR-β was reduced by 46% to 61% with 0.75 mg/kg cediranib. Additional selectivity was showed versus Flt-3, CSF-1R, EGFR, FGFR1, and FGFR4. Collectively, these data indicate that cediranib is a potent pan-VEGFR kinase inhibitor with similar activity against c-Kit but is significantly less potent than PDGFR-α and PDGFR-β. Mol Cancer Ther; 10(5); 861–73. ©2011 AACR.

Biofluids such as synovial fluid, blood plasma, and saliva contain several proteins which impart non-Newtonian properties to the biofluids. The concentration of such protein macromolecules in biofluids is regarded as an important biomarker for the diagnosis of several health conditions, including cardiovascular disorders, joint quality, and Alzheimer's. Existing technologies for the measurements of macromolecules in biofluids are limited; they require a long turnaround time, or require complex protocols, thus calling for alternative, more suitable, methodologies aimed at such measurements. According to the well-established relations for polymer solutions, the concentration of macromolecules in solutions can also be derived via measurement of rheological properties such as shear-viscosity and the longest relaxation time. We here introduce a microfluidic rheometer for rapid simultaneous measurement of shear viscosity and longest relaxation time of non-Newtonian solutions at different temperatures. At variance with previous technologies, our microfluidic rheometer provides a very short turnaround time of around 2 min or less thanks to the implementation of a machine-learning algorithm. We validated our platform on several aqueous solutions of poly(ethylene oxide). We also performed measurements on hyaluronic acid solutions in the clinical range for joint grade assessment. We observed monotonic behavior with the concentration for both rheological properties, thus speculating on their use as potential

ObjectiveChronic diseases, such as inflammatory bowel disease (IBD), can impact negatively on education and social development. Examining the impact of IBD on school/college attendance for children and young people (CYP) is vital to provide targeted support to patients, families and schools.MethodsWe performed a cross-sectional survey to determine the school/college attendance rates, the reasons for absence related to IBD and facilitators or barriers to school/college attendance. In a subset of patients followed up locally, we performed a detailed review of hospital attendance data to assess healthcare burden.ResultsTwo hundred and thirty-one questionnaires were given to CYP with IBD aged 5–17 years. Response rate was 74% (final sample 169). The median school/college attendance rate was 92.5%, significantly lower than all children in England (95.2%). 39.6% of children with IBD were persistently absent, defined nationally as missing 10% or more of school. Only five children (3%) had a 100% attendance record. Increasing age and use of monoclonal therapy were predictors of poor school attendance. Concerns about feeling unwell at school/college, access to toilets, keeping up with work and teachers’ understanding of IBD are the main issues for CYP with IBD. There was a significant negative correlation between number of days in hospital and school attendance.ConclusionIBD has a significant impact on school/college attendance, with hospital attendance, disease burden and school difficulties being major factors. Employing strategies to minimise healthcare burden and developing a partnership between health and education to support children with IBD will serve to facilitate school/college attendance.

Background The first wave of the COVID-19 pandemic in the UK severely restricted our regional paediatric GI outpatient services affecting our ability to assess patients in hospital, further compounded by distance of travel of patients (An audit form 2019 showed 70% of patients endoscoped were from outside the local, rather than Southampton area). The issue was further compounded by some DGH’s, who stopped offering the calprotectin test due to COVID-19 infection risk to the staff. Although home based calprotectin kits are also available, families using them have reported their use cumbersome and difficult to process tests at home. In addition, calprotectin results from other laboratories may be difficult to access. These limitations led to the development of a new regional service, in which samples taken at home are posted to the hub hospital laboratory (where the IBD clinic is based) for Calprotectin testing. Aim To study the benefits of offering a service for posting faecal samples for calprotectin testing to a hub laboratory. Methods Children (0–18 years) with IBD in the Wessex region, UK needing a calprotectin test were given postal faecal calprotectin packs (PFCP), either by hand in clinic or posted to their home. Each PFCP contained a labelled specimen bottle with immunology request form, bio-packaging box, sealable return bag (UN3373 compliant) with attached freepost label and instruction sheet. A Calprotectin cut off level of Results 63 patients (M=34, 54% & F=29, 46%) were given PFCP between 27th July & 5th of Nov 2020 with 52.4% posted PFCP and 47.6% given PFCP by hand in the paediatric GI clinic. The patients resided at a mean distance of 41.6 miles (1 SD = 24.1 miles) as the crow flies from the hospital. A mean of 25 days (1SD = 10 days) were taken from posting/handing of PFCP to the lab test result being obtained. The PFCP was returned by 50 patients (79.4% compliance) with a diagnosis of Crohn’s disease 34.9%, UC 28.6%, IBDU 7.9%, oral ulcers 4.8% and 23.8% of patients referred for endoscopy with IBD like symptoms. 30% of the patients with IBD (15/50) posting the PFCP had an abnormal test result. This led to a change in management in 40% of the patients. In the patient group referred with suspected IBD only 1/15 patients had an abnormal calprotectin test. 70% of patients with a normal test were able to be reassured without further investigation. Conclusion This is the first reported series, offering to a large region a robust method for samples to be taken at home and posted to a central hub laboratory for calprotectin testing during the COVID-19 pandemic. Test results were readily available, being performed in the same hospital site as the IBD clinic. Compliance with the new PFCP remains high with 80% using the new PFCP service, with value in early identification of patients who may not have much in terms of symptoms and avoidance of endoscopy in others with a normal calprotectin.

Background Management of paediatric Crohn’s disease (CD) presents significant challenges. Escalation of therapy to biologics or a ‘top-down’ approach, with early introduction of biologics, is common. Anti-TNF agents are widely used, but the use of ustekinumab is still limited. Ustekinumab is a human monoclonal antibody targeting the p40 subunit of both IL-12/-23. Ustekinumab has recently emerged as an alternative treatment option in children with failure of response to anti-TNF alpha treatment and those developing intolerable side effects on anti-TNF treatment including psoriasis. Aims Data on ustekinumab efficacy in paediatric IBD are limited. We report our experience on the use of this monoclonal antibody in paediatric IBD at a tertiary GI service in Wessex. Methods Retrospective review of all paediatric patients (≤ 18 years) receiving ustekinumab for the management of their IBD. Data was collected by reviewing patients’ electronic medical records and available results. Only those who had the treatment for at least 26 weeks were included. Steroid free remission were the primary outcomes of this study and resolution of psoriasis (where applicable) as a secondary outcome measure. Results Between November 2017- November 2020, 12 patients (M:F=6:6) patients were identified who were commenced on ustekinumab for the treatment of their IBD; 9 patients with CD and 3 with IBDU- Crohn’s like. One patient was excluded as the duration of treatment was The median duration between diagnosis and initiation of treatment with ustekinumab was 104 weeks and median duration of treatment with ustekinumab at the time of the review was 60 weeks (26–160 weeks). All patients received standard anti-TNF alpha treatment prior to ustekinumab. (All 11 patients received infliximab, 7 patients received both infliximab and adalimumab, and 4 patients were escalated directly from infliximab to ustekinumab). The key indications for considering ustekinumab were primary non-response (N=5, 45%), secondary loss of response (N=3, 27%) and anti-TNF-alpha induced psoriasis. Six patients (54%) developed psoriasis while on treatment with anti-TNF alpha. Three patients (27%) were switched to ustekinumab primarily in view of anti-TNF-alpha induced psoriasis. Steroid-free remission rates were (81%) at 26 weeks (N=9), (90%) at 52 weeks and 100% thereafter in 5 individuals who remained on ustekinumab over 1 year at the last review. No significant side-effects were reported in any patient. 85% of patients (N=5:6) who were identified with psoriasis have shown good response to switching treatment from anti-TNF to ustekinumab. Conclusions This data suggests that ustekinumab is a useful and a safe treatment option in children with IBD refractory to standard monoclonal therapy and in those developing intolerable anti-TNF alpha induced side-effects, psoriasis in particular. Larger studies from multiple centres would be required to develop standardised pathways for the use of this promising monoclonal agent for the management of paediatric IBD.

Resistance to targeted EGFR inhibitors is likely to develop in EGFR-mutant lung cancers. Early identification of innate or acquired resistance mechanisms to these agents is essential to direct development of future therapies. We describe the detection of heterogeneous mechanisms of resistance within populations of EGFR-mutant cells (PC9 and/or NCI-H1975) with acquired resistance to current and newly developed EGFR tyrosine kinase inhibitors, including AZD9291. We report the detection of NRAS mutations, including a novel E63K mutation, and a gain of copy number of WT NRAS or WT KRAS in cell populations resistant to gefitinib, afatinib, WZ4002, or AZD9291. Compared with parental cells, a number of resistant cell populations were more sensitive to inhibition by the MEK inhibitor selumetinib (AZD6244; ARRY-142886) when treated in combination with the originating EGFR inhibitor. In vitro, a combination of AZD9291 with selumetinib prevented emergence of resistance in PC9 cells and delayed resistance in NCI-H1975 cells. In vivo, concomitant dosing of AZD9291 with selumetinib caused regression of AZD9291-resistant tumors in an EGFRm/T790M transgenic model. Our data support the use of a combination of AZD9291 with a MEK inhibitor to delay or prevent resistance to AZD9291 in EGFRm and/or EGFRm/T790M tumors. Furthermore, these findings suggest that NRAS modifications in tumor samples from patients who have progressed on current or EGFR inhibitors in development may support subsequent treatment with a combination of EGFR and MEK inhibition. Cancer Res; 75(12); 2489–500. ©2015 AACR.

Crohn's disease is a chronic inflammatory bowel condition that affects more than 115,000 people in the UK. This article focuses on Crohn's disease in adolescents. Management of the condition in this group should address adolescent-specific characteristics and treatment goals. Key elements include optimising growth, pubertal development and social functioning, including education. The condition can affect an individual's mental and emotional wellbeing significantly, as well as their physical health. As adolescence is a time of great change, the additional burden of a chronic illness can prove difficult to manage. The authors provide information on the presentation of Crohn's disease in adolescence and insights into the particular issues encountered by this group.

This article suggests that silence has been undervalued and neglected in group analysis. This includes the way it is split off from theoretical group paradigms, which traditionally hold verbal communication as central to therapeutic change. At the core of this argument is an assertion that speech and silence are inseparable and need to be understood in relationship to each other. The article also explores how silence might emerge in groups both helpfully and problematically. Using clinical examples, from her training group, the author describes two different kinds of group silences, which might be loosely identified as ‘mature’ and ‘primitive’. She discusses the complex dialectic between speech and silence emerging in these vignettes, suggesting that this is what underpins the therapeutic exchange and developments in these examples and in analytic groups generally.

Aims To study the provision of paediatric liver services in a regional centre in the South of England Methods Children with liver diseases seen in paediatric Hepatology clinics over the last 5 years were included in the study. Details of demographics, underlying diagnosis, investigations and treatments were extracted in a database. Results There are two paediatric liver clinics in Southampton; one in conjunction with the supra-regional liver centre in London and the other a regional transitional clinic, with 3 consultants (supraregional, regional and transitional), dietetic, specialist nursing support and representation of the national charity Children Liver Disease Foundation in the clinics. Overall 223 children (Median Age: 12.2 years IQR: 6.8–17.1 years) were seen in the services (M:F 54.7:45.3) over the last 5 years (45 patients diagnosed/year). Children were referred from 11 hospitals across the network (Hampshire, Dorset, Wiltshire and Sussex). The most common 3 diagnoses seen in the clinics were Alpha-1-Antitrypsin deficiency (17%), Viral Hepatitides (11.7%) and Autoimmune liver disease (9.9%). With an increasing national incidence, 9.4% of the children presented with fatty liver and 15 patients with liver transplant are seen in the services. Nearly a third of patients graduated from the joint supra-regional clinic to the regional transitional clinic with provision of local radiology, bile duct stenting, bile duct botox and variceal banding services (endoscopic). Conclusions This study reflects the busy work load of a regional liver paediatric gastroenterology centre in the South of England. The paediatric liver services bridge an important gap between DGHs and supra-regional centres providing family centred specialist care for children with liver diseases, at convenience and closer to their homes. With an increasing new patient referral from DGHs and nearly third of patients transitioning to adult services, the need of a regional hepatology transitional clinic cannot be underestimated which can work in tandem with the joint supra-regional liver clinics providing uninterrupted smooth transition and continuity of care. With these increasing responsibilities, the role of a regional paediatric GI centre needs to be better recognised in managing paediatric liver patients, as currently highlighted in the NHS England specialist liver disease services contract.

Recent advances in next-generation sequencing have revealed that majority of the human genome is transcribed into long and short RNA (ncRNA) transcripts. Many ncRNAs function by interacting with proteins and forming regulatory complexes. RNA-protein interactions are vital in controlling core cellular processes like transcription and translation. Therefore identifying proteins that interact with ncRNAs is central to deciphering ncRNA functions. Here we describe an RNA-protein pull-down assay, which enables the identification of proteins that interact with an RNA under study. As an example we describe pull-down of proteins interacting with ncRNA XIST, which assists in the recruitment of the polycomb-repressive complex-2 (PRC2) and drives X-chromosomal inactivation.

Cediranib is a potent inhibitor of the VEGF receptor (VEGFR)-2 and VEGFR-3 tyrosine kinases. This study assessed the activity of cediranib against the VEGFR-1 tyrosine kinase and the platelet-derived growth factor receptor (PDGFR)-associated kinases c-Kit, PDGFR-α, and PDGFR-β. Cediranib inhibited VEGF-A–stimulated VEGFR-1 activation in AG1-G1-Flt1 cells (IC50 = 1.2 nmol/L). VEGF-A induced greatest phosphorylation of VEGFR-1 at tyrosine residues Y1048 and Y1053; this was reversed by cediranib. Potency against VEGFR-1 was comparable with that previously observed versus VEGFR-2 and VEGFR-3. Cediranib also showed significant activity against wild-type c-Kit in cellular phosphorylation assays (IC50 = 1–3 nmol/L) and in a stem cell factor–induced proliferation assay (IC50 = 13 nmol/L). Furthermore, phosphorylation of wild-type c-Kit in NCI-H526 tumor xenografts was reduced markedly following oral administration of cediranib (≥1.5 mg/kg/d) to tumor-bearing nude mice. The activity of cediranib against PDGFR-β and PDGFR-α was studied in tumor cell lines, vascular smooth muscle cells (VSMC), and a fibroblast line using PDGF-AA and PDGF-BB ligands. Both receptor phosphorylation (IC50 = 12–32 nmol/L) and PDGF-BB–stimulated cellular proliferation (IC50 = 32 nmol/L in human VSMCs; 64 nmol/L in osteosarcoma cells) were inhibited. In vivo, ligand-induced PDGFR-β phosphorylation in murine lung tissue was inhibited by 55% following treatment with cediranib at 6 mg/kg but not at 3 mg/kg or less. In contrast, in C6 rat glial tumor xenografts in mice, ligand-induced phosphorylation of both PDGFR-α and PDGFR-β was reduced by 46% to 61% with 0.75 mg/kg cediranib. Additional selectivity was showed versus Flt-3, CSF-1R, EGFR, FGFR1, and FGFR4. Collectively, these data indicate that cediranib is a potent pan-VEGFR kinase inhibitor with similar activity against c-Kit but is significantly less potent than PDGFR-α and PDGFR-β. Mol Cancer Ther; 10(5); 861–73. ©2011 AACR.

Primary ciliary dyskinesia is a rare inherited condition affecting the movement and structure of the cilia in various areas of the body, including sinuses, ears and airways. Since 2006, three centres for diagnosis and research in England have been raising awareness and funding for primary ciliary dyskinesia's diagnosis and treatment. Other areas in the UK have their own arrangements and can refer to one of the English centres. This article discusses the condition, introduces the centres and advises on where to get more information. The author concludes that paediatric nurses are in a unique position to learn about and increase awareness of the condition to help prevent unnecessary ear, nose and throat surgeries and permanent lung damage.

First- and second-generation EGFR TKIs are established first line therapy for patients with NSCLC with activating mutations in EGFR. Unfortunately, patients ultimately develop disease progression with acquisition of a second-site EGFR T790M mutation in more than half of cases. This has led to the development of third generation EGFR TKIs which inhibit both the EGFRm+ and T790M mutations in preclinical models and are showing activity in TKI-resistant patients in Phase I studies. Despite the potential improvements brought by third generation EGFR-TKIs, advanced EGFRm+ tumor cells will still remain highly adaptable and the inevitability of further resistance will limit the effectiveness of these drugs. As such, the identification of resistance mechanisms to these agents is essential to guide future therapeutic strategies and identify novel:novel combinations. To interrogate resistance to AZD9291, we have generated panels of EGFRm+ cell lines resistant to gefitinib (first generation TKI) and EGFRm+ and EGFRm+/T790M cell lines resistant to afatinib and AZD9291 (second and third generation TKIs, respectively). Subsequently, we characterised the cell lines using a variety of molecular profiling techniques including Next Generation Sequencing (NGS), Affymetrix gene expression analysis, and phenotypic profiling following pharmacological modulation by small molecule inhibitors of canonical signaling pathways. The effects on cell survival across the range of resistant models by a panel of pathway inhibitors indicated that resistance to the EGFR inhibitors, in particular AZD9291, is frequently associated with increased sensitivity to selumetinib (AZD6244; ARRY-142886) (MEK1/2 inhibitor), suggesting that ERK signaling is commonly reactivated to circumvent inhibition of the EGFR pathway. Molecular characterisation of the panel of cell lines suggests a range of different resistance mechanisms may be responsible for reactivation of ERK signaling, including a decrease in negative regulators of ERK such as DUSP6 or an epithelial to mesenchymal transition consistent with previous observations. Collectively, these data suggest that combining an EGFR TKI with a MEK inhibitor could prevent or delay resistance and drive superior duration of benefit from these agents. Citation Format: Cath Eberlein, Laura Ratcliffe, Lucy O'Brien, Katie Al-Khadimi, Henry Brown, Paul Fisher, Daniel Stetson, Zhongwu Lai, Gayle Marshall, Claire Barnes, Kenneth Thress, Brian Dougherty, William Pao, Darren Cross. Investigating resistance to AZD9291. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1722. doi:10.1158/1538-7445.AM2014-1722